Despite the great advances in cancer therapy, there is great interest in the development of new anticancer agents with novel mode of action, because of the development of resistance to existing anticancer drugs by tumor cells. The peptides are still of great interest as new therapeutic drugs, because of the role as mediators of important biological functions and its unique intrinsic properties that make them particularly attractive therapeutic agents. The peptides show a high biological activity associated with low toxicity and high specificity. The benefits arising from these features include a high specificity of binding to the desired target, minimizing the adverse drug-drug interaction and reported lower tissue accumulation reducing the risk of complications due to intermediate metabolites (Vlieghe et al., 2010, Drug Discovery Today, 15:40-56). Currently, there are anti-cancer therapies that use peptides and/or small molecules with selectivity of binding to a specific target protein, which has an important biological function in cancer development. In a first scenario, these therapies can be targeted to inhibit specific protein function and cause the apoptosis of cancer cell, for example: Inhibitors of Heat Shock Proteins (HSP) (Sreedhar et al., 2004, Pharmacology & Therapeutics, 101:227-257); Tyrosine kinase inhibitors (Garrido et al., 2007, Rev Med Chil, 10:1327-1332). In most of the situations these proteins are considered aberrant in the malignant process, when compared with normal tissue.
In a second scenario, the drug binds to a protein target that may or may not be aberrant in the malignant process compared to normal tissue, in this case the signaling pathways that are activated in the process of malignancy are affected, for example: Inhibitors of deoxyribonucleic acid (DNA) replication, inhibitors of microtubule assembly and inhibitors of the NFkB transcription factor.
While the first scenario is highly effective in certain hematopoietic malignancies, most of these therapies have limited effectiveness in the complexity of solid tumors. By contrast, the second scenario includes some of the most effective and more toxic cancer drugs in the oncologic pharmacopoeia. For this reason, progress is needed in the search for new drugs that are becoming more selective and effective, minimizing its toxicity. In this regard the identification of new therapeutic targets and understanding their role in cancer development, will help to identify new mechanisms of drug resistance and facilitate the design of new drugs that retain greater activity and can be combined with the existing ones, decreasing their toxicity and increasing the life quality of patients with cancer. COMMD1 protein, previously known as MURR1 (van de Sluis et al., 2002, Human Molecular Genetics, 11:165-173) belongs to a new family of proteins, known by its acronym COMMD (Copper Metabolism gene MURR1 Domain, COMMD abbreviated). The ten members of the family proteins are highly conserved in pluricellular organisms and ubiquitously expressed, but the biological functions of most of its members are unknown. The key characteristic of this family is the presence of the COMM domain (Copper Metabolism Murr1 Domain), conserved and unique, comprising the amino acid residues 110-190 of the C-terminal region (Burstein et al., 2005, The Journal of Biological Chemistry, 280:22222-22232). COMMD1 has been implicated in diverse biological processes such as: the control of copper metabolism (Tao et al., 2003, Journal of Biological Chemistry, 278:41593-41596), regulation of intracellular transport of sodium (Biasio et al., 2004, Journal of Biological Chemistry, 279:5429-5434), inhibition of NFkB transcriptional factor (Maine et al., 2007, The EMBO Journal, 26:436-447), inhibition of the expression of genes regulated by the Hypoxia-Inducible Factor (HIF)-1α (van de Sluis et al., 2007, Molecular and Cellular Biology, 27:4142-4156).
COMMD1 shows physical interaction with the RelA (p65) subunit from the NFkB transcriptional factor, with the catalytic-α subunit from HIF-1α factor and with Delta ENaC in epithelial sodium channels. In all cases this interaction leads to the degradation of these “client” proteins through a mechanism that involves ubiquitination and proteasome degradation pathways. It has been shown that the COMM domain is involved in protein-protein interactions, both for protein “clients” of COMMD1, as well as for interactions among family members. There is a proposal for the three-dimensional structure of the N-terminal region of COMMD1, but still there is not available a tertiary structure for the COMM domain (Sommerhalter et al., 2007, Journal of Molecular Biology, 365:715-721).
COMMD1 basal expression in the cell is controlled by ubiquitination and proteasomal degradation through a series of leucine residues, located in the COMM domain (Maine et al., 2009, Biochemical Journal, 417:601-609). Recently, it has been reported that COMMD1 has a constitutive mechanism of transport cytoplasm-nucleus through nuclear export signals (NES) also located in its COMM domain. It is reported that a disruption in the leucine sequence and/or agents that inhibit the proteasomal degradation, generates an increasing in the expression of COMMD1 in the cells. In addition, the disruption of the NES sequences in COMMD1 increases the repression of the transcriptional activity of NFkB and HIF-1α factors (Muller et al., 2009, Traffic, 10:514-527).
The cancer cells over-expressing different proteins, such as the protein XIAP (X-linked inhibitor of apoptosis) and secretory clusterin (sCLU). Both proteins promote degradation of COMMD1 and facilitate the activation of NFkB and tumor cell survival. It is reported that proteasome inhibitors, such as MG132 (Shirley et al., 2005, Neoplasia, 7:1104-1111; Zhou et al., 2009, Cancer Research, 69:8284-8292) showed antitumor effect by inhibiting the mechanism of ubiquitination and proteasome degradation. Compounds that bind to XIAP induce apoptosis by blocking the inhibitory effect of this protein on the activation of caspase-3 and caspase-9 (Vogler et al., Cancer Research, 2009, 69:2425-2434). It is suggested that the interference ribonucleic acid (RNAi) designed to inhibit the function of sCLU has antitumor effect, by stabilizing a cytoplasmic inhibitor of NFkB factor known as I-kB (Zoubeidi et al., 2010, Molecular Cancer Research, 8:19 30 119-130).
In the international patent application WO 07/095867, the essence of the invention is related to peptides derived from the 32-51 region of the LALF protein (Limulus anti-lipopolysaccharide factor), in which amino acid substitutions were made to ensure dissociation of the LPS-binding capacity and increase the antitumor and immunomodulatory activities. One of these peptides is the peptide named L2. In addition, another invention (International Application PCT/CU2008/000006) reveals the cell-penetrating ability of the above mentioned peptides. However, in such inventions is not disclosed nor suggested the mechanism of action of such peptides. At present there are a number of therapies to treat cancer (chemotherapy, radiotherapy, immunotherapy, etc), many of which are in clinical trials. However, there are still drawbacks associated with these therapies such as: the low selectivity, toxicity and development of drug resistance. Another important aspect to consider in this area is the selection of biomarkers, useful as diagnostic and/or as predictors of drug efficacy. Therefore, there remains a need to investigate and discover new molecules that are useful in the treatment and/or diagnosis of cancer, and the design of drugs more selective and effective with less toxicity.